KR100442718B1 - Process for the Preparation of the Mesylate Salt Trihydrate of 1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol - Google Patents

Abstract

The present invention provides a compound of the following formula (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol compound A method for producing mesylate trihydrate. The present invention also includes methods for enantiomeric splitting and isolation of (D)-(-)-tartrate salts of compounds of formula (I).

Description

Process for the preparation of mesylate salt trihydrate of 1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol {Process for the Preparation of the Mesylate Salt Trihydrate of 1- (4-Hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol}

The present invention provides a compound of formula 1, (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol It relates to a process for preparing its mesylate trihydrate from-(-)-tartrate salt.

<Formula 1>

Compound of formula 1, (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol is NMDA (N-methyl -D-aspartic acid) receptor antagonist with potent activity, epilepsy, anxiety, cerebral ischemia, muscle spasm, multiple infarct dementia, traumatic cerebral injury, pain, AIDS-related dementia, hypoglycemia, migraine, amyotrophic lateral sclerosis, drugs and Useful for the treatment of alcoholism, drug and alcohol withdrawal symptoms, mental illness, incontinence and degenerative CNS (central nervous system) disorders such as seizures, Alzheimer's disease, Parkinson's disease and Huntington's disease.

The mesylate trihydrate form of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol is, by its nature, anhydrous mesyl It is better as an active therapeutic agent than rate. Mesylate trihydrate is a more stable crystalline form than the anhydrous mesylate salt, and therefore in fact has a longer shelf life. In addition, trihydrate is less prone to destruction of the crystal structure due to the incorporation of water in the crystal. U.S. Patent No. 6,008,233 discloses mesylate salt tertiary of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol Carbohydrates, anhydrous mesylate salts and free bases, and methods for their preparation are described.

Free bases, anhydrous mesylates and methods for their preparation are also mentioned in US Pat. No. 5,185,343, generally issued February 9, 1993. Their use for the treatment of these specific disorders is specifically described in US Pat. No. 5,272,160, issued December 21, 1993, and US designated international application, filed May 18, 1995 and published as WO96 / 06081. Reference is made to patent application PCT / IB95 / 00380. United States designation, filed May 26, 1995 and published as WO96 / 37226, for use in combination with a compound that can restore and restore the balance of excitatory feedback from the dorsal side nucleus to the cortex to treat Parkinson's disease. In the international patent application PCT / IB95 / 00398. The above US patents and patent applications are incorporated by reference in their entirety.

The present invention

(i) D-(-)-tart of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol Dissolving the late salt in an aqueous methanesulfonic acid solution, and

(ii) (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidine-1 comprising separating methanesulfonate salt trihydrate from solution The present invention relates to a process for preparing methanesulfonate salt trihydrate of -yl) -1-propanol.

<Formula 1>

In the above method, D-(-)-of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol The molar ratio of methanesulfonic acid to tartrate salt is preferably 1.3 to 1.0. More preferably, D-(-) of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol The molar ratio of methanesulfonic acid to tartrate salt is 1.10 to 1.05, most preferably 1.10 to 1.08.

In the process of the invention, the aqueous methanesulfonic acid solution of step (i) is preferably prepared using pyrogen-free water.

The invention also

(i) dissolving the racemate mixture comprising the compounds of formulas (1) and (2) in aqueous methanol in the presence of D-(-)-tartaric acid, and

(ii) (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1 -Separating the D-(-)-tartrate salt of propanol from the solution

Methanesulfonate salt water of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol It relates to any of the aforementioned methods of making a cargo.

<Formula 1>

In this process, it is preferred that the water content of aqueous methanol is 5-20%. More preferably, in embodiments of the present invention the water content of aqueous methanol is 7-10%. The present invention also relates to a method for optically dividing and isolating the (D)-(-)-tartrate salt of the compound of formula (1).

The invention also relates to compounds of formula (1), i.e. (1S, 2S) -1- (4-hydroxy, wherein the ratio of (1S, 2S) -enantiomer to (1R, 2R) -optical symmetry is at least 97%. D-(-)-tartrate salt of phenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol. More preferably, the ratio of (1S, 2S) -enantiomer to (1R, 2R) -optical symmetry is at least 98%.

<Formula 1>

Mesylate salt trihydrate of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol is in single crystal form and water A white crystalline solid that has good solubility in water (25 and 15 mg / mL in buffered aqueous solutions of pH 3 and 7, respectively). Mesylate salt trihydrate is known to be produced when anhydrous mesylate salt is left to equilibrate in an environment with a relative humidity of 81%. For example, as in US Pat. No. 6,003,233, the prior art process for the preparation of mesylate salt trihydrate requires the free base as a starting material, which requires an additional step of isolating and drying the free base compound of formula 1 after the mirror image separation in the overall synthesis process. I had to use it.

However, in the present invention, (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1 without going through a free base Mesylate salt trihydrate can be prepared directly from the D-(-)-tartrate salt of -propanol. The D-(-)-tartrate salt used above is 1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol racemate Is the product of optical symmetric splitting. Thus, according to the present invention, the mesylate salt can be synthesized more efficiently in fewer steps.

The process of the present invention also provides D-(-of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol. Improved methods of partitioning the) -tartrate salt. Prior art, such as US Pat. No. 6,003,233, describes the splitting of racemates of 1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol For this purpose, selective crystallization from anhydrous methanol was carried out using optically active tartrate salts, almost all of which enantiomer purity was acceptable with (1S, 2S) of at least 97% by subsequent reslurrying and / or recrystallization. Was achieved. Thus, the present invention provides a method with higher efficiency that eliminates repetitive purification steps in the overall synthetic route.

The method of the present invention is shown in the following schemes.

In Scheme 1, the benzyl protected racemic ketone compound represented by formula (3) was reacted with NaBH ₄ in ethanol at 40-50 ° C. for 6-7 hours, or potassium in tetrahydrofuran at 10-20 ° C. for 1-2 hours. Reduction of the Selectide (CalSelect K), or any other suitable reagents and conditions known to those skilled in the art, to obtain a mixture of threo and erythro isomers, wherein the treo isomer is co-reacted Predominantly at least about 80:20 in the mixture. Ethanol or THF solvent should not contain significant amounts of water, i.e. 0.2 to 0.5% or more. After actual isolation in the solvent, a treo component can be obtained which is almost 90% of the product of the treo orientation, ie the racemic mixture of the compound of formula 4a (ie, formulas 4aa and 4ab). Starting materials of the formula (3) are obtained by the process described in the above-mentioned US Pat. No. 6,008,233, the content of which is incorporated herein by reference in its entirety.

In Scheme 2 below, the benzyl group is selected from the racemate of the threo compound of formula 4a by any method known to those skilled in the art, preferably at 45-50 ° C., preferably under hydrocracking conditions, more preferably approximately 5-6 Removal is by exposure to palladium on carbon in the presence of hydrogen gas in wet tetrahydrofuran for time. In such cases, other effective methods of removing benzyl groups are known to those skilled in the art.

The racemic mixture of the optical symmetry of Formulas 1 and 2, the product of this reduction reaction, is then partitioned through the formation and selective crystallization of the D-(-)-tartrate salt. (1S, 2S) -1- (4 D-(-)-tartrate (Formula 5a) of -hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol is a racemate (Formula 1 and After heating the anhydrous methanol solution of 2) to approximately 50-55 degreeC, it is prepared directly by slowly adding the aqueous D-(-)-tartaric acid solution. The mixture is then heated to approximately 60-65 ° C. and a small amount of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) The D-(-)-tartrate salt of -1-propanol (Formula 5a) may optionally be added to promote the formation of the D-(-)-tartrate salt. The mixture is then maintained at reflux temperature (60-65 ° C.) for about 4 hours during which a thick suspension is formed. The slurry is cooled slowly and the solid is collected by filtration and washed with methanol. In this way (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) having an enantiomer and diastereomeric impurity of 2% or less Obtain the D-(-)-tartrate salt of -1-propanol. The ratio of water to methanol should be adjusted so that the water / methanol is 5-20%, preferably 7-10% in the final solution. Table 1 below demonstrates a significant improvement in the enantiomer purity of the D-(-)-tartrate salt when using aqueous methanol rather than anhydrous methanol as solvent. As shown in Table 1 below, in the method using anhydrous methanol as a solvent, (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4- with similar level of purity Up to two reslurrying or recrystallizations may be required to obtain the D-(-)-tartrate salt of phenylpiperidin-1-yl) -1-propanol.

Fractionation of racemates (compounds 1 and 2) with D-(-)-tartaric acid in methanol versus aqueous methanol D-tartaric acid (molar equivalent) Solvent (mL / g crude compound 1/2) reaction Reslurry Needed (1R, 2R) -enantiomer% Time (h) Temperature (℃) Yield (%) 1.0 Methanol (20) 3 65 78 One 1.8 1.0 Methanol (20) 3 65 78 One 2.0 1.0 Methanol (20) 5 65 76 2 1.2 1.0 Methanol (20) 5.5 65 73 2 1.7 1.03 Methanol (18) 3.5 65 88 0 2.5 1.03 Methanol (18) / Water (1.6) 3.5 65 80 0 1.1

(1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl)-almost free of corresponding (1R, 2R) and other diastereomers 1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl)-in aqueous methanol to form the D-(-)-tartrate salt of 1-propanol The cleavage of the racemate of 1-propanol is illustrated in Example 1 below. Example 2 provides a comparative method using anhydrous methanol as a solvent.

In Scheme 3 above, the D-(-)-tartrate salt is dissolved in water in the presence of 1.00 to 1.15 molar equivalents, preferably 1.05 to 1.10 molar equivalents of methanesulfonic acid, and the mixture is heated to approximately 60 to 65 ° C. The solution is then filtered to remove any foreign particulate matter, thereby providing (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl Mesylate salt trihydrate of) -1-propanol is formed directly from the D-(-)-tartrate salt. The warmed solution is then slowly cooled to 15-20 ° C. to give a dark white suspension, further cooled to 0-5 ° C. and then granulated at 0-5 ° C. for one hour. The product is isolated by filtration, then washed with cold water (0-5 ° C.) and then the mesylate salt is dried under inert atmosphere. Table 2 shows the molar equivalents of methanesulfonic acid relative to (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol The preparation of mesylate salt trihydrate carried out by varying the proportions of is shown.

Preparation of Compound of Formula 6 from Compound of Formula 5a equivalent weight water yield Enantiomers Diastereomer Compound (5a) (mol) CH ₃ SO ₃ H (mol) Volume (mL / g 5a) Compound (6) Early final Early final 1.0 1.0 3.5 89.0% (cloudy) 1.7% 0.19% 0.4% 0.13% 1.0 1.05 3.5 90.4% (cloudy) 1.7% 0.05% 0.4% 0.08% 1.0 1.10 3.5 93.8% 1.7% 0.05% 0.4% 0.08% 1.0 1.15 3.25 92.4% 2.5% 0.07% 0.2% - 1.0 1.10 4.0 84.8% 3.2% 0.18% - <0.1% 1.0 1.15 3.25 87.0% 4.4% 0.68% 0.2% 0.18% 6, recrystallization 1.5 91.9% 0.68% 0.1% 0.18% 0.02%

Mesylate salt trihydrate has selective neuroprotective activity, similar to anhydrous mesylate and free base, depending on its anti-ischemic activity and its ability to block excitatory amino acid receptors. Preferred methods for assessing neuroprotective activity of the compounds of the invention are described in Ismail A. Shalaby, et al., J. Pharm. Exper. Ther., 260, 925 (1992). This document is incorporated by reference in its entirety and is described below.

Cell culture

Hippocampal cells from 17-day-old fetal mice (CD, Charles River Breeding Laboratories, Inc., Wilmington, Mass.) Were harvested from PRIMARIA culture plates (Falcon Co. ), 2 mM glutamine, 21 mM glucose, penicillin / streptomycin (500 U each), 10% fetal calf serum (1-7 days) and 10% horse serum for 2-3 weeks on Lincoln Park, NJ) Incubate in serum-containing culture medium (minimum essential medium containing non-essential amino acids) containing (1 to 21 days). Cells are plated on 96-well microtiter plates at a concentration of 80,000 cells per well or plated on 24-well culture plates at a density of 250,000 cells per well. Cultures are grown in a wet CO ₂ tissue culture incubator containing 5% CO ₂ /95% air at 37 ° C. Proliferation of non-neuronal cells was 20 μM of uridine and 20 μM of 5-fluoro-2-deoxyuridine (Sigma Chemcal Co., St. Louis, Missouri, USA) by 6-8 days of culture. Control by adding Culture medium is replaced with fresh solution every 2-3 days.

Glutamate toxicity

Cultures are assessed for glutamate toxicity after 2-3 weeks of initial plating. The culture medium was removed and the cultures were CSS (in millimolar, NaCl, 12-; KCl, 5.4; MgCl ₂ 0.8; CaCl ₂ , 1.8; glucose, 15; and 4- (2-hydroxyethyl) -1- Rinse twice with piperazineethanesulfonic acid, 25 mM (pH 7.4)). The culture is then exposed to different concentrations of glutamate for 15 minutes (37 ° C.). After this incubation, the cultures are rinsed three times with glutamate free CSS and two times with fresh serum-free culture medium. The culture is then incubated in avascular culture medium for 20 to 24 hours. The compound to be tested is added 2 minutes prior to and 15 minutes of exposure to glutamate. In some experiments, compounds are added at different time points after glutamate exposure, followed by incubation for 20 to 24 hours.

Cell viability is typically assessed by measuring the activity of the cytoplasmic enzyme LDH 20 to 24 hours after excitatory toxin exposure. LDH activity is measured from the culture medium of each 96-well of the microtiter plate. 50 μl of a sample of medium is added to an equal volume of sodium phosphate buffer (0.1 M, pH 7.4) containing 1.32 mM sodium pyruvate and 2.9 mM NADH. The 340 nm absorbance of the total reaction mixture for each of the 96 wells is monitored by an automatic spectroscopic microtiter plate reader (Molecular Devices, Menlo Park, Calif.) Every 5 seconds for 2 minutes. Absorbance is calculated automatically using the IBM SOFTmax program (Version 1.01; Molecular Devices), which is used as an indicator of LDH activity.

Morphological evaluation of neuronal cell growth is measured using a phase contrast microscope. Since good phase contrast images cannot be obtained with 96-well culture plates, cells cultured on 24-well plates are used for this purpose. Quantitatively, both culture platings are equally sensitive to glutamate toxicity and show a 2-3 fold increase in LDH activity 24 hours after exposure to 0.1-1.0 mM glutamate.

reagent

DTG is available from Aldrich Chemical Co. (Milwaukee, WI) and haloperidol is Research Biochemicals Inc. (Research Biochemicals Inc., Natick, MA). Spurmin is available from Sigma Chemicals Company, St. Louis, Missouri. Equine and fetal bovine serum can be purchased from Hyclone, Logan, Utah. Culture media, glutamine and penicillin / streptomycin can be purchased from Gibco Co., Grand Island, NY.

Data analysis

Neurotoxicity can be quantified by measuring the activity of LDH present in the culture medium 20 to 24 hours after exposure to glutamate. Increased LDH activity in culture media is associated with the destruction and degeneration of neurons (Koh and Choi, 1987). Since actual levels of LDH vary with different cultures, data is typically expressed in association with buffered sister wells in the same culture plate. To obtain an indicator of LDH activity from glutamate and drug treated cultures, the LDH value of the control culture is subtracted from the value of the treatment group. Data on drug treatment is expressed as percent increase in LDH induced with 1 mM glutamate (or NMDA) for each experiment. The concentration of NMDA antagonist (IC ₅₀ ) required to recover 50% of the LDH increase induced by excitatory toxins is calculated from the stored results of three independent experiments using log-probit analysis.

Selective neuroprotective anti-ischemic and excitatory amino acid blocking activity of the mesylate salt trihydrate of the present invention may include degenerative CNS disorders such as seizures, Alzheimer's disease, Parkinson's disease and Huntington's disease; Selected from epilepsy, anxiety, cerebral ischemia, muscle spasms, multiple infarct dementia, traumatic brain injury, pain, AIDS-related dementia, hypoglycemia, migraine, amyotrophic lateral sclerosis, drug and alcoholism, drug and alcohol withdrawal symptoms, mental illness and incontinence It is useful for the treatment of disorders.

In the systemic treatment of the disorder, the dosage is typically about 0.02 to 250 mg per kg body weight per day (typically 0.001 to 12.5 g per day for a person weighing 50 kg) in a single or divided dosage form, regardless of the route of administration. A more preferred dosage range is about 0.15 mg to about 250 mg per kg body weight per day. Of course, dosages outside this range may be prescribed by the attending physician depending on the exact nature of the disease and the condition of the patient. Oral route of administration is generally preferred. However, if the patient cannot swallow or oral absorption worsens, the preferred route of administration is parenteral (i.m. or i.v.) or topical administration.

Mesylate salt trihydrate can be administered in the form of a pharmaceutical composition with a pharmaceutically acceptable vehicle or diluent. Such compositions generally employ solid or liquid vehicles or diluents, as appropriate, in the form of a desired dosage form, such as tablets, hard or soft gelatin capsules for oral administration, suspensions, granules, powders, and the like, for parenteral administration. It is formulated in a conventional manner in the form of a death penalty solution or suspension, and in the form of a solution, a lotion, an ointment, a salves or the like for topical administration.

The following examples illustrate the process of the present invention and the process for preparing the compounds of the present invention. The melting point is not corrected. NMR data are reported in ppm (δ) and, unless otherwise noted, are based on deuterium lac signal from sample solvent (percent deuterium dimethyl sulfoxide (d ₆ -DMSO). Commercially available reagents were used without further purification.

<Example 1>

Partition of 1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol with D-(-)-tartaric acid in aqueous methanol

1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol racemate (78.0 kg, 207.7 mol) and anhydrous methanol (1,223 L) Was added to a clean reactor maintained under a nitrogen atmosphere. The mixture was stirred and heated to 50-55 ° C. After maintaining the solution at 50-55 ° C. for 1 hour, a solution of D-(−)-tartaric acid (32.1 kg, 214 mol) in water (105 L) was added over 10 minutes. The solution is heated to 60-65 ° C. and (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl in methanol (0.5 L) D-(-)-tartrate salt of) -1-propanol (50 g) was added. This solution was kept at reflux temperature (60-65 ° C.) for 4 hours during which a thick suspension formed. The slurry was cooled to 30 to 35 ° C. over 1.5 hours and then filtered at 30 to 35 ° C. The cake was washed with methanol (204 L) and dried in vacuo at 40-45 ° C. for 20-30 hours. D-(-)-tartrate salt of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol ( 39.4 kg) was isolated in 40% by weight yield (80% of theory). [a] _D ²⁵ + 35.2 (0.0185, water). Chiral HPLC showed that the solid contained 1.2% of (1R, 2R) -enantiomer and 0.8% of (1R, 2S)-and (1S, 2R) -diastereomer.

<Example 2>

Partitioning of 1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol with D-(-)-tartaric acid in methanol anhydrous

In a suitable flask maintained under a nitrogen atmosphere, 1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol (189.5 g, 0.58 mol) and methanol (3.8 L) was added. The mixture was heated to 50-55 ° C. and then D-(-)-tartaric acid (87.0 g, 0.58 mol) was added. This mixture was heated at reflux (about 65 ° C.) for 5 hours. The slurry was cooled to 30-35 ° C. and then granulated at 30-35 ° C. for 1 hour. The product was filtered off and the cake was washed with fresh methanol (135 mL). Wet cakes were sampled and subjected to chiral HPLC analysis to determine enantiomer impurity concentrations. The wet cake was suspended in methanol (1.6 L) and the resulting slurry was heated at reflux (approximately 65 ° C.) for 5 hours under a nitrogen atmosphere. The slurry was cooled to 30-35 ° C., granulated at 30-35 ° C. for 1 hour and then filtered. The filter cake was washed with methanol (136 mL) and dried at 40-45 ° C. vacuum for 18-24 hours. Samples were analyzed by chiral HPLC. D-(-)-tartrate salt of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol ( 118.0 g) was obtained in 43 wt% yield. Sometimes, as shown in Table 1 above, additional methanol reslurrying is required to reduce the amount of (1R, 2R) -enantiomer impurities to 2.5% or less.

<Example 3>

Preparation of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propane mesylate trihydrate

D-(-)-tartrate salt of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol ( 5.0 g, 10.5 mmol), water (17.5 mL), and methanesulfonic acid (1.05 g, 11.0 mmol) were mixed in a 50 mL, three necked round bottom flask under a nitrogen atmosphere. The slurry was heated to 60-65 ° C. to obtain a solution and then filtered. The filtrate was slowly cooled to 15-20 ° C. over 1 hour to give a dark white suspension. The slurry was further cooled to 0-5 ° C. and then granulated at 0-5 ° C. for 1 hour. The product was filtered and the cake washed with 2.5 mL of cold water (0-5 ° C.) and then dried at 20-25 ° C. under nitrogen sweep. (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol mesylate trihydrate (4.53 g) as white crystals It was isolated with the total yield of 90.4% as a solid. The physical chemistry of the isolated trihydrate was the same as the standard sample.

¹ H NMR (d ₆ -DMSO) δ 9.58 (s, 1H), 8.91 (s, 1H), 7.48 (m, 2H), 7.35 (m, 2H), 7.21 (m, 3H), 6.77 (d, J = 8.5 Hz, 2H), 6.35 (s, 1H), 5.52 (s, 1H), 4.58 (d, J = 8.1 Hz, 1H), 3.40 (m, 11H), 2.63 (m, 1H), 2.3 (s , 3H), 1.78 (m, 2H), 0.95 (d, J = 6.6 Hz, 3H).

¹³ C NMR (d ₆ -DMSO) δ 158.13, 148.61, 132.27, 129.27, 128.80, 127.51, 125.26, 115.89, 72.12, 68.89, 66.30, 47.40, 42.91, 35.71, 35.37.

Elemental Analysis C ₂₀ H ₂₅ NO ₃ .CH ₃ SO ₃ H. ₃ H ₂ O. Calculated Value: C, 52.81; H, 7.39; N, 2.93; S, 6.71

Found: C, 52.77; H, 7. 50; N, 2.94; S, 6.96.

α _D = + 54.5 ° (anhydrous basis).

(1S, 2S) -1- (4-hydroxyphenyl) -2 when low pyrogen water and pyrogen-free conditions are introduced into the process. -(4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol mesylate trihydrate is adapted for use in the preparation of parenteral drug products. Table 2 reports the preparation of trihydrate using methanesulfonic acid in various equivalents. It is to be noted that when methanesulfonic acid is used in low equivalents (1.0 to 1.05), the trihydrate, the product when dissolved in water, contains residual fog (a small amount of insoluble matter) which is not acceptable for parenteral preparations.

According to the invention, D-(-) of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol Mesylate trihydrate of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol directly from tartrate salt Can be manufactured. In addition, according to the present invention, by using aqueous methanol as a solvent, the ratio of (1S, 2S) -enantiomer to (1R, 2R) -optical symmetry is effectively 97 without repeated purification steps in the whole synthesis route. D-(-)-tartrate of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol which is at least% The salt can be partitioned.

Claims (13)

(i) dissolving the D-(-)-tartrate salt of the compound of formula 1 in an aqueous methanesulfonic acid solution, and (ii) separating methanesulfonate salt trihydrate from solution Method of producing a methanesulfonate salt trihydrate of the compound represented by the following formula (1) comprising a. <Formula 1> The process of claim 1 wherein the molar ratio of methanesulfonic acid to the D-(-)-tartrate salt of the compound of formula 1 is in the range of 1.3 to 1.0. The process of claim 1 wherein the molar ratio of methanesulfonic acid to the D-(-)-tartrate salt of the compound of formula 1 is in the range of 1.10 to 1.05. The process of claim 1 wherein the molar ratio of methanesulfonic acid to the D-(-)-tartrate salt of the compound of formula 1 is in the range of 1.10 to 1.08. The method of claim 1, wherein the aqueous methanesulfonic acid is prepared using pyrogen-free water. The method of claim 1, (i) dissolving the racemate mixture comprising the compounds of formulas (1) and (2) in aqueous methanol in the presence of D-(-)-tartaric acid, and (ii) separating the D-(-)-tartrate salt of the compound of formula 1 from solution How to further include. <Formula 1> <Formula 2> 6. The process of claim 5 wherein the water content of aqueous methanol is between 5 and 20%. 6. The process of claim 5 wherein the water content of aqueous methanol is 7-10%. (i) dissolving the racemate mixture comprising the compounds of formulas (1) and (2) in aqueous methanol in the presence of D-(-)-tartaric acid, and (ii) separating the D-(-)-tartrate salt of the compound of formula 1 from solution Method for producing a D-(-)-tartrate salt of the compound of formula 1 comprising a. <Formula 1> <Formula 2> 10. The process of claim 9 wherein the water content of aqueous methanol is between 5 and 20%. 10. The process of claim 9 wherein the water content of aqueous methanol is 7-10%. delete delete